Sphingomyelin increases drug sensitivity in human pancreatic cancer cells in vitro and in vivo. Free

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Background: Pancreatic cancer is a notoriously drug-resistant disease. We sought to determine whether human pancreatic cancer cells, in culture and as xenografts, could be made more chemosensitive through manipulation of sphingolipid metabolism. Ceramide, produced from the hydrolysis of sphingomyelin (SM), is an intracellular lipid second messenger capable of inducing apoptosis. We, and others, have proposed that a reduced availability of SM, whether because of reduced total cellular or specific subcellular pools of SM, can lead to drug resistance. By supplementing chemotherapy with SM, we hypothesized that efficacy could be improved. Methods: We examined the ability of SM, at levels displaying little or no cytotoxicity by itself, to reduce the in vitro IC₅₀ values of a variety of chemotherapeutic agents having differing mechanisms of action. We also examined the ability of SM to improve GEM efficacy in the Panc1 s.c. tumor xenograft model. Results: In human Panc1 cells, we found synergism between SM and 5-fluorouracil (5FU), carboplatin, doxorubicin (DOX), gemcitabine (GEM), and irinotecan; additive effects with dacarbazine and fludarabine; and antagonism with taxol. Panc1 tumors, grown in SCID mice to 0.1-0.2 cm³, were treated as follows: GEM (6 mg i.p. once weekly for 3 weeks), SM (10 mg i.p. every day for 5 days/week x 3 weeks), GEM + SM (as for each drug individually with the GEM dose given with the third SM injection). These regimens were repeated for a second cycle after a 1-week rest. The results indicate that this tumor model is highly resistant to clinically-relevant doses of GEM. Additionally, there was no effect of SM when used as a single agent. However, the combination of GEM with SM resulted in a significant inhibition of tumor growth (P<0.01 compared to GEM alone), with resulting improvement in survival. Median survival times were 38.3 days (untreated), 38.8 days (SM), 39.8 days (GEM) and 54.7 days (GEM + SM combination) (P<0.01 for the comparison of the combination group to GEM alone). Conclusions: These in vitro and in vivo results indicated that SM enhances the effects of several drugs and that, in the treatment of xenografted pancreatic cancer with GEM, SM significantly improved the antitumor effects.